Lovastatin attenuates cyclosporine inhibition of potassium channels in cortical collecting duct cells

Abstract

Statins may benefit patients receiving cyclosporine A (CsA) treatment after organ transplantation. However, there is little in vitro data to support the use of statins to reduce the harmful effects of CsA such as hyperkalemia. Our cell‐attached patch‐clamp data showed that CsA inhibited an inwardly rectifying potassium channel in the apical membrane of mouse cortical collecting duct principal cells (mpkCCDc14 line) and that lovastatin attenuated the inhibition. Phosphatidylinositol‐3,4,5‐trisphosphate (PIP3) is a lipid which is known to stimulate inward rectifier potassium channels. Under normal conditions, PIP3 is synthesized in the basolateral membrane and can pass tight junctions to diffuse to the apical membrane. It appears that this diffusion is blocked by CsA because confocal microscopy showed that CsA reduced PIP3 in the apical membrane, but increased PIP3 in the basolateral membrane. Lovastatin reversed the effects of CsA on PIP3 levels. We also found that CsA increased, but lovastatin decreased, the transepithelial resistance by altering the levels of zonula occludens‐1 (ZO‐1) and cholesterol in tight junctions. Using scanning ion conductance microscopy, we showed that the apical membrane of mpkCCDc14 cells contains cellular protrusions in the area near tight junctions. CsA significantly increased the height of the protrusions. In contrast, lovastatin eliminated the protrusions and even caused a modest depression between the cells. These data suggest that lovastatin can abolish CsA inhibition of potassium channels in the apical membrane of CCD cells by altering the lateral diffusion of PIP3 which possibly controlled by both ZO‐1 and cholesterol levels in tight junctions. The present study provides one molecular mechanism for the previous suggestion that statins benefit CsA treatment of patients with organ transplantation.